Derivatives of 5-nitro-2-furaldehyde



United States Patent 3,396,163 DERIVATIVES 0F S-NITRO-Z-FURALDEHYDEWilfred Herbert Hook, Brooklands, Sale, and Jack Raymond Green,Roniiley, England, assignors to Geigy Chemical Corporation, Greenburgh,N.Y., a corporation of Delaware No Drawing. Filed Sept. 10, 1965, Ser.No. 486,532 Claims priority, application Great Britain, Sept. 12, 1964,37,390/ 64 4 Claims. (Cl. 260-240) ABSTRACT OF THE DISCLOSURE nitroZ-furfurylideneamino-triazolones of the wherein R is hydrogen, orhydroxy-lower alkyl, halogenlower alkyl, lower alkanoyl, lower alkenoylor lower alkoxycarbonyl, and R is hydrogen or lower alkyl, are disclosedto have useful antimicrobial properties, being valuable antibacterial,antifungal, anthelminthic or coccidiostatic agents for external use inhuman or veterinary medicine. 4 (5-nitro-2' furfurylideneamino)1:2:4-triazolone-S is particularly useful.

The present invention relates to substituted heterocyclic organiccompounds, and in particular to nitrofuryl derivatives ofaminotriazolones.

According to the present invention, there is provided aS-nitro-Z-furfurylidene-amino-triazolone of the formula wherein R ishydrogen, or hydroxy-lower alkyl, halogenlower alkyl, lower alkanoyl,lower alkenoyl or lower alkoxycarbonyl, and R is hydrogen or loweralkyl.

The alkyl as mentioned in the definition of R may be straightorbranched-chained and may be, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tertiary butyl, n-amyl or isoamyl. If R isalkyl substituted by halogen, the halogen may be fluorine or iodine butis preferably chlorine or bromine. If R is alkanoyl oralkenoyl, this maybe, for exarnle, formyl, acetyl, propionyl, n-butyryl, n-valeryl orn-caproyl or crotonyl. If R is alkoxycarbonyl, this is preferablymethoxycarbonyl or ethoxycarbonyl. If R, is lower alkyl, this may be,for example, methyl, ethyl etc. up to amyl.

The invention also provides a process of producing a 5-nitro-Z-furfurylidene-amino-triazolone of Formula I, which comprisescondensing S-nitro-Z-furaldehyde, or a derivative yieldingS-nitro-Z-furaldehyde under the conditions of the reaction, with asubstituted 4-amino-triazolone having the Formula II or a salt thereof,wherein R and R have the significance as given under Formula I.

The condensation may be effected, for instance, by heating the5-nitro-2-furaldehyde, or functional derivative thereof, with thesubstituted 4-amino-triazolone, or salt 3,396,163 Patented Aug. 6, 1968thereof, in the presence of an organic solvent substantially inert underthe reaction conditions. Conveniently the reactants may be heatedtogether in the solvent at the boiling point under reflux. The organicsolvent may be, for example, ethanol. The reaction mixture may be heatedfor a duration within a wide range, but may conveniently be heated forfrom a few minutes up to 1 hour.

The substituted 4-amino-triazolones used as reactants in this process ofthe invention, having the Formula II wherein R is hydrogen and R ishydrogen or lower alkyl, may be produced, for example, by reactingcarbohydrazide with the corresponding alkyl or aralkylortho-monocarboxylate having the Formula III wherein R is hydrogen orlower alkyl and R is lower alkyl or aralkyl.

Preferred alkyl or aralkyl ortho-monocarboxylates of Formula III have Ras methyl, ethyl, propyl, isoproyl or benzyl. The reaction may beeffected, for instance, by refluxing together the ortho-ester HI andcarbohydrazide, and removing the alcohol R OH which is formed,conveniently by distillation. The alkyl ortho-monocarboxylate may be anethyl ortho-monocarboxylate, for example ethyl ortho-formate, ethylortho-acetate or ethyl orthopropionate.

Substituted 4-amino-triazolones used as reactants in the process havingthe Formula II where R is hydroxysubstituted alkyl, the alky beingstraightor branchedchain and containing at least two carbon atoms, maybe produced by reacting the corresponding halide having the Formula IV RX (IV) with the corresponding arylidene-substituted compound andhydrolysing the grouping A=N- to an amino group, wherein X is chlorine,bromine or iodine, A represents an arylidene group, preferably abenzylidene group, M represents sodium, lithium, or potassium, butpreferably sodium, R is hydroxy-substituted alkyl, the alkyl beingstraightor branched-chain and containing at least 2 carbon atoms, and Rhas the significance as given under Formula I.

The present invention also provides a process of producing a5-nitro-2-furfurylideneamino-triazolone of Formula I, wherein Rrepresents alkanoyl or alkenoyl, which comprises acylating a5-nitro-furfurylidene-amino-triazolone of Formula I wherein R representshydrogen.

The acylation may be carried out using a conventional acylating agent,for instance, by heating with the anhydride or mixed anhydride or acidchloride of the corresponding monocarboxylic acid R -OH, for example,with the anhydride of acetic, propionic, n-butyric, n-valeric orn-caproic acid or a mixed anhydride thereof or a mixed anhydride offormic acid. Conveniently the reactants are heated together at theboiling point of the mixture under reflux.

The present invention also provides a process of producing aS-nitro-2-furfurylidene-amino-triazolone of Formula I, wherein Rrepresents hydroxymethyl, which comprises hydroxymethylating aS-nito-Z-furfurylidene-aminotriazolone of Formula I, wherein Rrepresents hydrogen, with formaldehyde or with a substance yieldingformaldehyde under the conditions of the reaction. Thehydroxymethylation may be carried out, for instance, by heating withaqueous formaldehyde solution, conveniently by bo'ili-ng together underreflux. The concentration of formaldehyde in the aqueous solution ispreferably from'l% to 10% by weight based on the weight of the solution.

The S-nitro 2 furfurylidene-amino-triazolone compounds of Formula I,wherein R is halogen-substituted alkyl, may be produced byhalogen-exchange of the hydroxy group of the correspondinghydroxyalkyl-substituted-S-nitro-2-furfurylidene-amino-triazolone. Thehalogen-exchange reaction may be carried out by a conventional method,for instance, by reacting with thionyl chloride, thionyl bromide,phosphorus pentachloride or phosphorus pentabromide.

The S-nitro 2 furfurylidene-amino-triazolone compounds of Formula I,wherein R is alkoxycarbonyl, may be produced by carbalkoxylating thecorresponding 5- nitro 2 furfurylidene-amino-triazolone of Formula Iwherein R is hydrogen. The reaction may be carried out, for example, byreacting with an alkyl chloroformate, conveniently in the presence, asreaction medium, of pyridine and/or in the presence of an organicsolvent substantially inert under the conditions of the reaction.

The 5-nitro 2 furfurylidene-amino-triazolone compounds of the presentinvention may also be produced by nitration of the correspondingZ-furfurylidene-amino-triazolones having the Formula VI wherein R and Rhave the significance as given under Formula I.

The nitration may be carried out with nitric acid under conditionsconventional in nitrating substituted furyl derivatives, for instance,in the presence of a water binding agent; the water binding agent maybe, for example, sulphuric acid, but is preferably acetic anhydride. Ifdesired, a proportion of acetic acid may be present in the reactionmixture. The nitration is preferably carried out at a temperature notexceeding 15 C. using concentrated or fuming nitric acid.

The 5-nitro 2 furfurylidene-amino-triazolne compounds of Formula Iwherein R represents hydrogen may also be produced by cyclising the-nitro-2-furaldehyde-carbohydrazone having the Formula VII R2 (VI) withan alkyl or aralkyl ortho-monocarboxylate having the Formula III whereinR and R have the significance as given above under Formula 111.

The reaction may be carried out, for instance, by heating together,preferably by boiling under reflux, and removing the alcohol R OH whichis formed, conveniently by distillation.

The compounds of the invention have useful pharmacological and inparticular antimicrobial properties, being valuable antibacterial,antifungal, anthelminthic or coccidiostatic agents for external use inhuman or veterinary medicine. The compounds may also be used to protectan organic material susceptible to bacterial, fungal or other microbialdeterioration by contacting with, impregnation in or otherwise treatingthe material with the compounds. Compounds of Formula I wherein at leastone of the groups R and R is hydrogen are particularly valuableantimicrobial agents, especially the compound of Formula I wherein bothR and R are hydrogen. In living organisms they are active, for example,against general staphylococcal infectious.

Accordingly, the invention also provides a composition comprising anantimicrobially effective proportion of a5-nitro-2-furfurylidene-amino-triazolone of Formula I and apharmacologically acceptable solid carrier or liquid diluent.

The invention also provides a method of protecting an organic materialsusceptible to bacterial, fungal or other microbial attack whichcomprises treating the material with a5-nitro-2-furfurylidene-amino-triazolone of Formula I. The organicmaterial may be, for instance, a natural or synthetic polymericmaterial, a proteinaceous or carbohydrate substance, or a natural orsynthetic fibre or textile material formed therefrom.

The following examples further illustrate the present invention.

EXAMPLE 1 To a solution of 10 g. of 4-amino-1:2:4-triazolone-5 in 120ml. of normal aqueous hydrochloric acid was added 14.1 g. of5-nitro-2-furaldehyde in 200 ml. of ethanol. The mixture was heated toreflux for a short time and then allowed to cool slowly to roomtemperature. The crystalline yellow solid which formed was collected byfiltration, recrystallised from dimethyl formamide and dried in vacuumat 100 C. The product was 4-(5'-nitro-2-furfurylidene-amino)-l:2:4-triazolone-5, having melting point 216 C.with decomposition.

EXAMPLE 2 The procedure described in Example 1 was carried out using3-methyl-4-amino-1:2:4-triazolone-5 instead of 4-amino-1:2:4-triazolone-5, the reaction conditions being otherwiseessentially the same.

The product was3-methyl-4-(5-nitro-2'-furfurylideneamino)-l:2:4-triazolone-5, havingmelting point 267 C. with decomposition.

The 3-methyl-4-amino-l:2:4-triazolone-5 used as reactant was prepared asfollows:

A mixture of 78 g. of ethyl ortho-acetate and 25 g. of carbohydrazidewas refluxed for 6 hours. The ethanol formed in the reaction was removedby distillation, finally under reduced pressure, and crude3-methyl-4-amino- 1:2:4-triazolone-5 was obtained as a residue havingmelting point 130 C.

EXAMPLE 3 The procedure described in Example 1 was carried out using 3-ethyl-4-amino-l:2:#triazolone-5 instead of 4- amino-1z2z4-triazolone-5,the reaction conditions being otherwise essentially the same.

The product was 3-ethyl-4-(5'-nitro-2'-furfurylideneamino)-l:2:4triazolone-5, having melting point 240 C. with decomposition.

The 3-ethyl-4-amino-1:224-triazolone-5 used as reactant was prepared asfollows:

A mixture of g. of ethyl ortho-propionate and 30 g. of carbohydrazidewas refluxed for 6 hours. The ethanol formed in the reaction was removedby distillation, finally under reduced pressure, and3-ethyl-4-amino-lz2z4- triazolone-S was obtained as a yellow syrup whichwas used without further purification for reaction with 5-nitro-2-furaldehyde.

EXAMPLE 4 A mixture of 15 g. of 4-(5'-nitro-2'-furfurylideneamino)-lz2z4-triazolone-5 and 50 ml. of acetic anhydride was heated at refluxfor 1 minute. After cooling and standing, the fawn crystals werecollected, washed with ethanol and dried in vacuum at C.

The product wasl-acetyl-4-(5-nitro-2'-furfurylidene-amino)-l:2:4-triazolone-5, havingmelting point 205 C.

EXAMPLE 5 The procedure described in Example 4 was carried out usingpropionic anhydride instead of acetic anhydride, the reaction conditionsbeing otherwise essentially the same.

The product was1-propionyl-4-(5'-nitro-2-furfurylideneamino)-1:2:4-triazolone-5, havingmelting point 204 C.

EXAMPLE 6 The procedure described in Example 4 was carried out usingn-butyric anhydride instead of acetic anhydride, the reaction conditionsbeing otherwise essentially the same.

The product was1-n-butyryl-4-(5'-nitro-2'-furfurylidene-amino)-1:2:4-triazolone-5,having melting point 174 C.

EXAMPLE 7 The procedure described in Example 4 was carried out usingn-valeric anhydride instead of acetic anhydride, the reaction conditionsbeing otherwise essentially the same.

The product wasl-n-valeryl-4-(5'-nitro-2'-furfurylidene-amino)-1z2z4-triazolone-5,having melting point 154 C.

EXAMPLE 8 The procedure described in Example 4 was carried out usingn-caproic anhydride instead of acetic anhydride, the reaction conditionsbeing otherwise essentially the same.

The product was 1 n caproyl 4 (5 nitro 2'furfurylidene-amino)-1:2z4-triazolone-5, having melting point 144 to 145C.

EXAMPLE 9 The procedure described in Example 4 was carried out using 3methyl 4 (5' nitro 2' furfurylidene amino) 1:2:4 triazolone 5 instead of4 (5' nitro- 2-furfurylidene-amino)-1:2:4-tIia2olone-5, the reactionconditions being otherwise essentially the same.

The product was l-acetyl-3-methyl-4-(5'-nitro-2-furfurylidene-amino)-1:2:4-triazolone-5, having melting point 203 to 205C.

EXAMPLE 10 The procedure described in Example 4 was carried out using 3methyl 4 (5' nitro 2 furfurylidene amino) 1:2:4 triazolone 5 instead of4 (5' nitro- 2 furfurylidene amino) 1:2:4 triazolone 5 and propionicanhydride instead of acetic anhydride, the reaction conditions beingotherwise essentially the same.

The product was 1 propionyl 3 methyl 4 (5'- nitro 2 furfulylidene amino)1:2:4 triazolone 5, having melting point 205 C.

EXAMPLE 11 The procedure described in Example 4 was carried out using 3ethyl 4 (5' nitro 2' furfurylidene amino 1:2:4 triazolone 5 instead of 4(5' nitro 2'- furfurylidene-amino)-1z2z4-triazolone-5, the reactionconditions being otherwise the same.

The product was 1 acetyl 3 ethyl 4 (5 nitro-2-furfurylidene-a.mino)-1:2z4-triazolone-5, having melting point 170 to171 C.

EXAMPLE 12 The procedure described in Example 4 was carried out using3-ethyl-4-(5'-nitro-2 furfurylidene-amino)-1:2:4- triazolone-5 insteadof 4 (5-nitro-2' furfurylideneamino)-1:2:4-triazolone-5 and propionicanhydride instead of acetic anhydride, the reaction conditions beingotherwise essentially the same.

The product was 1-propionyl-3-ethyl4-(5'-nitro-2'-furfi1rylidene-arnino)-1z2z4-triazolone-5, having melting point 156 to158 C.

EXAMPLE 13 A mixture of 10.8 g. of4-(5'-nitro-2'-furfurylideneamino)-1:2:4-triazol0ne-5 and 565 ml. of 5%by weight aqueous formaldehyde solution was heated at reflux for 10minutes and then cooled to room temperature. The crystalline yellowsolid was collected by filtration, washed with ethanol and dried invacuum at 80 C.

The product was 1-hydroxymethyl-4-(5'-nitro-2'-furfurylideneamino)-1:2:4-triazolone-5, having melting point 189 C. withdecomposition.

EXAMPLE 14 The procedure described in Example 13 was carried out using3-methyl-4-(5-nitro-2-furfurylidene-amino)- 1:2:4-tr-iazolone-5 insteadof 4-(5'-nitro-2'-furfurylideneamino)-1:2z4-triazolone-5, the reactionconditions being otherwise essentially the same.

The product was 1-hydroxymethyl-3-methyl-4(5-nitro-2'-furfurylidene-amino)-1:2:4-triazolone 5, having melting point264 C. with decomposition.

EXAMPLE 15 The procedure described in Example 13 was carried out using3-ethyl-4-(5'-nitro 2-furfurylidene-amino)- 1:2:4-triazo1one-5 insteadof 4-(5'-nitro-2'-furfurylideneamino)-1:2z4-triazolone-5, the reactionconditions being otherwise essentially the same.

The product was 1-hydroxymethyl-3-ethyl-4-(5-nitro-2'-furfurylidene-amino)-1z2z4-triazolone-5, having melting point 172 to174 C. with decomposition.

EXAMPLE 1'6 5 g. of ethyl chloroformate were slowly added to asuspension of 7.7 g. of4-(5-nitro-2'-furfurylideneamino)-1a2z4-triazolon'e-5 in 78 ml. ofpyridine at 0 to 10 C. After stirring for one hour at 0 to 10 C., and 2/2 hours at C., the suspension was poured into 180 ml. of 2 Nhydrochloric acid solution with cooling.

The pale yellow solid which separated was collected by filtration andrecrystallised from :50 dimethyl formarnidezethanol. The product was1-ethoxycarbonyl-4-(5- nitro-2-furfurylidene-amino) -1 2 4-triazolone-5,having melting point 207 C. with decomposition.

EXAMPLE 17 A mixture of 5.6 g. of 1-hydroxymethyl-4-(5'-nitro-2-furfurylidene-amino)-1:2z4-triazolone-5, 4.2 g. of thionyl chlorideand 14 ml. of benzene were heated at refiux for 1 hour. After coolingthe reaction product, the yellow crystals that were formed werecollected by filtration, washed with benzene, recrystallised frombenzene and dried in vacuum at C.

The product was1-chloromethyl-4-(5'-nitro-2'-furfurylid-ene-amino)-1:2:4 triazolone-5,having melting point 154 to 156 C.

By carrying out the procedure using thionyl bromide instead of thethionyl chloride, the reaction conditions being otherwise essentiallythe same, the product obtained is 1-bromoethyl-4-(5' nitro-2'furfurylidene-amino)- 1 :2z4-triazolone-5.

By carrying out the procedure using thionyl chloride but using1-(2-hydroxyethyl)-4-(5"-nitro-2"-furfurylidenearnino)-1:2:4-triazolone-5instead of the l-hydroxymethyl-4-(5-nitro-2' furfurylideneamino)-1:2:4-triazolone-S, the reaction conditions being otherwiseessentially the same, the product obtained is1-(2'-ch'loroethyl)-4-(5"-nitro-2" furfurylidene amino)-1:2:4-triazolone-5.

EXAMPLE 18 A mixture of 2.13 g. of1-(5-nitrofurfury1idene)-carbohydrazide and 3.24 g. of triethylortho-formate were heated at C. for 36 :hours and then cooled to roomtemperature. The yellow solid which was obtained was collected byfiltration, washed with ethanol and dried in vacuum at 80 C.

4-(5'-nitr0-2'-furfurylidene amino)-1:2:4-triazolone- 5 was produced,being identical with the product of Example 1.

EXAMPLE 19 A mixture of 5 g. of crotonyl chloride and ml. of dimethylformamide was added to a suspension of 10 g. of4-(5'-nitro-2'-furfurylidene-amino)-1:2:4-tri- 7. azolone-S in 150 ml.of pyridine over minutes at to C. After stirring for 3 hours at roomtemperature, 250 ml. of water were added.

The crystalline solid which was formed was collected by filtration,recrystallised from a mixture of ethyl alcohol and dimethyl formamideand dried in vacuum at C. The product wasl-crotonyl-4-(5'-nitro-2'-furfurylidene-amino)-1:2:4 triazolone-S,having melting point 217 to 219 C.

EXAMPLE 20 5.1 g. of 50% sodium hydride in mineral oil were added to amixture of 20 g. of 4-benzylidene-amino- 1:2:4-triazolone-5 in 500 ml.of dimethyl formamide. The mixture was heated to reflux until all thesodium hydride h-ad reacted. 9.6 g. of 2-chloroethanol were then addedand the mixture heated with stirring at C. for 17 hours. The dimethylformamide Was then removed by distillation under reduced pressure andthe residue was steam distilled in the presence of dilute sulphuricacid. The resulting aqueous solution was reacted with a mixture of 10.6g. of 5-nitro-2-furalde'hyde in 100 ml. of ethyl alcohol.

The yellow crystalline solid produced was collected by filtration,recrystallised from .a mixture of ethyl alcohol and dimethyl formamideand dried in vacuum at 100 C. The product was 1-(2-hydroxyethyl)-4-(5-Intro-2"-furfurylideneamino)-1:2:4 triazolone-S, having melting point158 to 160.

EXAMPLE 21 wherein R is hydrogen or a hydroxy-lower alkyl, halogen-loweralkyl, lower alkanoyl, lower alkenoyl or lower alkoxy-carbonyl group,and R is hydrogen or lower alkyl.

2. A compound as defined in claim 1 wherein the group R is hydrogen orhydroxy-lower alkyl and R is hydrogen or lower alkyl.

3. A compound as defined in claim 1 wherein R is hydrogen and R ishydrogen or lower alkyl.

4. The compound of the formula References Cited CH=N UNITED STATESPATENTS 3,001,992 9/1961 Bellamy et al. 260-240 3,314,947 4/1967Benjamin 260-240 OTHER REFERENCES Zajdela et al.: Unio Intern. ContraCancrum, Acta vol. 20 (1-2), pp. 233-9 (1964).

JOHN D. RANDOLPH, Primary Examiner.

